Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation

• Published in: Blood 2005-12, Vol.106 (13), p.4381-4388
• Main Authors: Giaccone, Luisa, McCune, Jeannine S., Maris, Michael B., Gooley, Theodore A., Sandmaier, Brenda M., Slattery, John T., Cole, Scott, Nash, Richard A., Storb, Rainer F., Georges, George E.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Bone marrow, stem cells transplantation. Graft versus host reaction; Chimerism; Cytomegalovirus - physiology; Graft Rejection - immunology; Graft vs Host Disease - immunology; Graft vs Host Disease - pathology; Hematopoietic Stem Cell Transplantation; Humans; Immunomodulators; Liver - physiology; Liver Function Tests; Medical sciences; Middle Aged; Multiple Myeloma - pathology; Multiple Myeloma - surgery; Mycophenolic Acid - adverse effects; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - pharmacokinetics; Nausea - complications; Neutropenia - complications; Pharmacology. Drug treatments; Recurrence; Serum Albumin - metabolism; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Transplantation Conditioning; Transplantation, Homologous; Virus Activation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-06-2217

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 μg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 μg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 μg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 μg/mL could prevent graft rejection.